Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin

Nature. 1996 Oct 10;383(6600):535-8. doi: 10.1038/383535a0.


Enkephalins are endogenous opioid peptides that are derived from a pre-proenkephalin precursor protein. They are thought to be vital in regulating many physiological functions, including pain perception and analgesia, responses to stress, aggression and dominance. Here we have used a genetic approach to study the role of the mammalian opioid system. We disrupted the pre-proenkephalin gene using homologous recombination in embryonic stem cells to generate enkephalin-deficient mice. Mutant enk-/- animals are healthy, fertile, and care for their offspring, but display significant behavioural abnormalities. Mice with the enk-/- genotype are more anxious and males display increased offensive aggressiveness. Mutant animals show marked differences from controls in supraspinal, but not in spinal, responses to painful stimuli. Unexpectedly, enk-/- mice exhibit normal stress-induced analgesia. Our results show that enkephalins modulate responses to painful stimuli. Thus, genetic factors may contribute significantly to the experience of pain.

MeSH terms

  • Aggression*
  • Analgesia
  • Animals
  • Anxiety* / genetics
  • Cell Line
  • Enkephalins / deficiency
  • Enkephalins / physiology*
  • Female
  • Gene Targeting
  • Homozygote
  • Male
  • Mice
  • Mutagenesis
  • Pain*
  • Protein Precursors / deficiency
  • Protein Precursors / physiology*
  • Restriction Mapping


  • Enkephalins
  • Protein Precursors
  • preproenkephalin